Gastric Cardia Culprit in Barrett's Esophagus, Transformative Mechanism Identified

By Marilynn Larkin

August 18, 2021

NEW YORK (Reuters Health) - A series of laboratory experiments pinpointed the gastric cardia as the cellular origin of Barrett's esophagus (BE) and showed how undifferentiated BE cells can turn malignant, transforming into esophageal adenocarcinomas (EACs).

"Recently, new tools have become available to trace the ancestry of a single cell. You could call the methods that we used 21st century human archaeology," Dr. Rebecca Fitzgerald of the University of Cambridge, UK, told Reuters Health by email.

"We approached this study with an open mind," she said. "I personally was surprised when the data suggested Barrett's came from gastric cells. This had been suggested before, but the data was speculative and I had thought it might be more complicated. It looks from our results as though these cells can be reprogrammed when a molecular switch is activated."

"The second part of the research was to see how the new information we had generated at a single-cell level related to cancers in the lower esophagus and at the junction with the stomach," she explained. "In patients who present with swallowing difficulties who are shown to have a cancer, BE is only visible in about half the cases."

"When we compared the genes expressed in our large cancer database with those expressed by Barrett's cells, they are similar," she said. "In other words, the cancers without Barrett's look the same as those with Barrett's, suggesting they all develop from Barrett's cells."

As reported in Science, Dr. Fitzgerald and colleagues harvested tissues from both healthy and BE patient donors that spanned the gastroesophageal junction, including the esophageal submucosal glands, which had not been previously isolated,

Using a combination of single-cell transcriptomic profiling, in silico lineage tracing from methylation, open chromatin and somatic mutation analyses, and functional studies in organoid models, they showed that BE originates from gastric cardia that have been reprogrammed by turning on a switch in the c-MYC and HNF4A genes.

They also showed that EAC likely arises from undifferentiated BE cell types even when, as Dr. Fitzgerald indicated, BE is not seen at diagnosis.

Dr. Fitzgerald said, "It is still not fully known what triggers the gastric cells to transform into Barrett's cells which contain intestinal features (called goblet cells). Acid and bile reflux is known to be a major risk factor, and Caucasian, older men with increased BMI are also at more risk for Barrett's and, in turn, cancer."

"The next steps are to show the mechanisms at play all the way from reflux to Barrett's to cancer," she added. "BE cells do seem to be the key to cancer development. Therefore, a screening strategy to detect BE has the potential to prevent cancers of the esophagus and gastro-esophageal junction."

Dr. Karen Geboes of Universitair Ziekenhuis Gent in Belgium, coauthor of a related editorial, commented in an email to Reuters Health, "Generally, we detect BE well. Surveillance programs are in place, and if adherence is good, the results are good, meaning we can detect and treat dysplastic lesions and small tumors appropriately."

"However," she said, "it is difficult to recognize small segments of Barrett's mucosa, and surveillance depends on the recognition of small tumoral lesions, and also on finding dysplasia in random biopsies. Because of the patchy distribution of dysplasia, this can be missed. Also, there is interobserver variability in the pathological evaluation of dysplasia."

"A lot of work still needs to be done," she noted. "The experiments need to be replicated and validated in control groups, and other experiments should try to unravel the question of causality."

"If the findings are solid, we still need to bring the evidence from bench to bedside," she said. "This means we still need to make sure that the techniques looking for this cell - or a biomarker, a derivative - are easy to perform in clinic - i.e., fast and reproducible, among others."

"The experiments used in this study are very specific and time-consuming and not ready for practice yet," she added. "But things can evolve very rapidly in research and medicine and it is good to think in advance about how we might practically use new findings in clinic."

SOURCES: and Science, online August 12, 2021.